Many inflammatory processes directly impact the function of the central nervous system (CNS) and give rise to human diseases. For example, acute infection of the CNS can induce a variety of disease states such as meningitis and encephalitis. One of our main interests is to mechanistically define the impact of acute infections on the CNS and establish treatments to ameliorate the associated neurological disease. We study viral (lymphocytic choriomeningitis virus, vesicular stomatitis virus), parasitic (plasmodium berghei) and fungal (candida albicans) infections to identify the similarities and differences in how the immune system responds to these unique challenges. We also study sterile inflammatory responses (i.e., traumatic brain injury, glioblastoma, cerebrovascular injury) to provide insights into how CNS immune cells respond to damage in the absence of an infectious agent. To advance our understanding of neural-immune interactions during CNS inflammatory diseases, we utilize a contemporary approach referred to as intravital two-photon laser scanning microscopy (TPM), which allows us to watch immune cells operate in the living brain in real-time. This is accomplished by using fluorescently tagged immune cells and pathogens. Use of fluorescent tags allows us to study the dynamics of innate (e.g. microglia, monocytes, macrophages, neutrophils, dendritic cells) and adaptive (e.g. microbe-specific CD8 T cells, CD4 T cells, B cells) immune cells as a disease develops. We can also administer therapeutic compounds into the viewing window (transcranial delivery) and watch how this locally influences the inflammatory process in real-time. This powerful approach allows us to evaluate the efficacy of potential therapeutics at the site of disease. To gain novel insights into sterile immune responses in the brain, we developed a focal model of mild traumatic brain injury (mTBI) referred to as meningeal compression injury. Traumatic brain injuries in humans range from mild to severe and are quite diverse in nature. Our meningeal compression model reflects one type of injury among a broad spectrum. The injury is mild, focal, and occurs beneath a closed-skull. Importantly, this injury model is advantageous because it can be closely monitored by TPM and is amenable to local therapeutic manipulation. Using TPM we have defined the pathology and innate immune reaction to focal brain injury in real-time. Following mTBI, we observed that meningeal blood vessels and macrophages are damaged within the first 30 minutes. Some vessels become occluded while others leak their contents into the subarachnoid space. Importantly, the meningeal vascular pathology is comparable to what is observed in 50% of humans following mTBI. We also showed that the glial limitans becomes porous following injury due to destruction of astrocytes, resulting in leakage of cerebral spinal fluid and vascular material into the brain parenchyma. Destruction of the glial limitans may help explain the kinetics of cell death following mTBI. Cell death is first observed in the meninges and later spreads into the parenchyma over time as the glial limitans decays. We have also defined the innate immune response to mTBI from the injury's inception through the process of tissue remodeling and repair. The initial response to mTBI is characterized by a specialized microglia reaction in the brain parenchyma and the recruitment of myelomonocytic cells (neutrophils and monocytes) into the meninges. These responses are anatomically partitioned, with peripheral immune cells responding to the damaged meninges and brain-resident microglia tending to the injured parenchyma. Both immune reactions are initiated by purinergic receptor signaling and are neuroprotective. When the responses are inhibited, increased in cell death is observed. More recently, we have demonstrated that damaged vasculature in meninges shows a remarkable ability to repair following mTBI, both in rodents and humans. Importantly, this repair is dependent on the recruitment of two monocyte subsets from the blood that have non-overlapping functions. Classical inflammatory monocytes migrate to the center of meningeal lesions following mTBI and transform into macrophages that clean up dead cells. Non-classical monocytes, on the other hand, generate macrophages that localize around the lesion edge and promote angiogenesis via production of matrix metalloproteinase-2. In absence of these monocytes, the damaged meninges fail to properly repair, demonstrating the importance of peripheral innate immune cells in the healing process following mTBI. To pharmacologically manipulate the mTBI reaction locally, we have developed a new approach referred to as transcranial drug delivery. We discovered that the intact skull bone and sutures allows passage of low molecular weight compounds (<40,000 MW) into the underlying meninges and brain tissue. Using this approach, we have therapeutically neutralized one of the early mediators of mTBI lesion pathogenesis. We observed by TPM that reactive oxygen species (ROS) are generated almost immediately after injury. As a therapy, we applied the antioxidant, glutathione (GSH), transcranially (as late as 3 hours post-injury) and observed a >50% reduction in parenchyma cell death. This treatment also preserves meningeal macrophages, maintains integrity of the glial limitans, and markedly reduces the innate CNS inflammatory reaction. These data demonstrate that ROS are a major driver of mTBI pathogenesis and that there is a window of opportunity available for treatment of this condition. Delaying treatment increases the amount of irreparable brain damage and likely exposes the CNS to increasingly synergistic pathways of neurotoxicity. In addition to researching sterile injury responses like TBI, we also study acute CNS diseases induced by microbes. We have obtained novel insights into a potentially fatal disease referred to as cerebral malaria (CM). CM is a severe complication of Plasmodium falciparum infection in humans that results in thousands of deaths each year. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using an animal model, we set out to understand the mechanics of this disease. During the development of CM, we revealed that parasite-specific CD8+ T cells attack the surface of CNS blood vessels, which causes them to leak fluid into the brain and meninges. This results in brain swelling, which eventually damages the brainstem - a fatal process referred to as cerebral herniation. We were able to therapeutically remove the disease-causing T cells from cerebral blood vessels using anti-adhesion molecule (LFA-1 / VLA-4) antibodies. This treatment is highly effective and prevented fatal disease. These data suggest that it might be possible to treat CM in humans using two FDA approved anti-adhesion molecule antibodies.